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J. Biol. Chem., Vol. 282, Issue 47, 34510-34524, November 23, 2007

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The G12/13 Family of Heterotrimeric G Proteins and the Small GTPase RhoA Link the Kaposi Sarcoma-associated Herpes Virus G Protein-coupled Receptor to Heme Oxygenase-1 Expression and Tumorigenesis^*

María José Martín¹, Tamara Tanos², Ana Belén García³, Daniel Martin^¶, J. Silvio Gutkind^¶, Omar A. Coso, and Maria Julia Marinissen⁴

From the Instituto de Investigaciones Biomédicas A. Sols, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid 28029, Spain, the Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IFYBYNE-CONICET, 1428 Buenos Aires, Argentina, and ^¶Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892

Heme oxygenase-1 (HO-1), an inducible enzyme that metabolizes the heme group, is highly expressed in human Kaposi sarcoma lesions. Its expression is up-regulated by the G protein-coupled receptor from the Kaposi sarcoma-associated herpes virus (vGPCR). Although recent evidence shows that HO-1 contributes to vGPCR-induced tumorigenesis and vascular endothelial growth factor (VEGF) expression, the molecular steps that link vGPCR to HO-1 remain unknown. Here we show that vGPCR induces HO-1 expression and transformation through the G_12/13 family of heterotrimeric G proteins and the small GTPase RhoA. Targeted small hairpin RNA knockdown expression of G₁₂, G₁₃, or RhoA and inhibition of RhoA activity impair vGPCR-induced transformation and ho-1 promoter activity. Knockdown expression of RhoA also reduces vGPCR-induced VEFG-A secretion and blocks tumor growth in a murine allograft tumor model. NIH-3T3 cells expressing constitutively activated G₁₃ or RhoA implanted in nude mice develop tumors displaying spindle-shaped cells that express HO-1 and VEGF-A, similarly to vGPCR-derived tumors. RhoAQL-induced tumor growth is reduced 80% by small hairpin RNA-mediated knockdown expression of HO-1 in the implanted cells. Likewise, inhibition of HO-1 activity by chronic administration of the HO-1 inhibitor tin protoporphyrin IX to mice reduces RhoAQL-induced tumor growth by 70%. Our study shows that vGPCR induces HO-1 expression through the G_12/13/RhoA axes and shows for the first time a potential role for HO-1 as a therapeutic target in tumors where RhoA has oncogenic activity.

Received for publication, April 11, 2007 , and in revised form, September 14, 2007.

^* This work was supported by a grant from "Fundación Médica Mutua Madrileña" and by "Ministerio de Educación y Ciencia," Spain, Grant SAF2005-03020. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a collaboration fellowship from the Ministerio de Educación y Ciencia, Spain. The visit to Dr. Gutkind's laboratory (NIDCR, National Institutes of Health) was supported by Fundación Mutua Madrileña, Spain.

² This author's visit to our laboratory in Spain was supported by a grant from the Fundacion Mutua Madrileña, Spain.

³ A fellow from FINNOVA, Comunidad de Madrid.

⁴ To whom correspondence should be addressed: Instituto de Investigaciones Biomédicas A. Sols, Dept. de Bioquimica, Facultad de Medicina, Universidad Autonoma de Madrid, Arzobispo Morcillo 4, Madrid 28029, Spain. Tel.: 34-91-497-5464; E-mail: mjmarinissen{at}iib.uam.es.

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